Chronic hepatitis B virus infection is one of the most severe liver diseases in morbidity and death rate in the worldwide range. At present, pharmaceuticals for treating chronic hepatitis B (CHB) virus infection are classified to interferon α and nucleoside/nucleotide analogue, i.e. Lamivudine and Adefovir. However, these pharmaceuticals can not meet needs for doctors and patients in treating chronic hepatitis B virus infection because of their respective limitation. Entecavir (ETV) is referred to as 2′-cyclopentyl deoxyguanosine (BMS2000475) which belongs to analogues of Guanine nucleotide and is phosphorylated to form an active triple phosphate in vivo. The triple phosphate of entecavir inhibits HBV polymerase by competition with 2′-deoxyguanosine-5′-triphosphate as a nature substrate of HBV polymerase, so as to achieve the purpose of effectively treating chronic hepatitis B virus infection and have strong anti-HBV effects. Entecavir, [1S-(1α,3α,4β)]-2-amino-1,9-dihydro-9-[4-hydroxy-3-hydroxymethyl]-2-methylenecyclopentyl]-6H-purin-6-one, monohydrate, and has the molecular formula of C12H15N5O3.H2O and the molecular weight of 295.3. Its structural formula is as follows:

Entecavir was successfully developed by Bristol-Myers Squibb Co. of USA first and the trademark of the product formulation is Baraclude™, including two types of formulations of tablet and oral solution having 0.5 mg and 1 mg of dosage. Chinese publication No. CN1310999 made by COLONNO, Richard, J. et al discloses a low amount of entecavir and uses of the composition containing entecavir in combination with other pharmaceutically active substances for treating hepatitis B virus infection, however, the entecavir is non-crystal. In addition, its oral formulations such as tablet and capsule are made by a boiling granulating process. The process is too complicated to control quality of products during humidity heat treatment even though ensuring uniform distribution of the active ingredients.
The present inventors of the Chinese patent application CN200710004988.9 provides a crystal entecavir in an aqueous solution as active ingredients. It has been found that tablets and capsules produced by a crystal entecavir in an aqueous solution as active ingredients are more stable than that of amorphous entecavir under the conditions of light, high temperature and high humidity.
The object of the present invention is to provide an oral formulation of the composition containing a crystal entecavir and the method of preparing for the same. The method comprises uniformly mixing the active crystal entecavir with glidants (or lubricants), and then uniformly mixing with diluents, adhesives, disintegrants and lubricants, and then directly tabletting or filling capsule. Comparing with processes of wet granulation, boiling granulating or spray drying granulation, the method is simpler in operation, more suitable for industrial production and control of product quantity, reduced energy consumption, and reduced production cost.